Magnesium alloy implants with controlled degradation

ABSTRACT

Stents or scaffolds made from magnesium or magnesium alloys including additives or barrier coatings that modify the corrosion rate of the stent are disclosed. Methods of forming barrier coatings that modify the corrosion rate of the stent are disclosed.

This application is a divisional of application Ser. No. 13/436,538filed on Mar. 30, 2012, which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to implantable medical devices, in particularstents, fabricated from corrodible metals.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, which areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel.

A stent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices, which function to hold open and sometimesexpand a segment of a blood vessel, or other anatomical lumen, such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty in the vascular system. “Restenosis”refers to the reoccurrence of stenosis in a blood vessel or heart valveafter it has been treated (as by balloon angioplasty, stenting, orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, to a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

In the case of a balloon expandable stent, the stent is mounted about aballoon disposed on the catheter. Mounting the stent typically involvescompressing or crimping the stent onto the balloon. The stent is thenexpanded by inflating the balloon. The balloon may then be deflated andthe catheter withdrawn. In the case of a self-expanding stent, the stentmay be secured to the catheter via a constraining member such as aretractable sheath or a sock. When the stent is in a desired bodilylocation, the sheath may be withdrawn which allows the stent toself-expand.

The stent must be able to satisfy a number of mechanical requirements.First, the stent must be capable of withstanding the structural loads,namely radial compressive forces, imposed on the stent as it supportsthe walls of a vessel. Therefore, a stent must possess adequate radialstrength. Radial strength, which is the ability of a stent to resistradial compressive forces, is due to strength and rigidity around acircumferential direction of the stent. Radial strength and rigidity,therefore, may also be described as hoop or circumferential strength andrigidity.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by pulsatile bloodflow. For example, a radially directed force may tend to cause a stentto recoil inward. Generally, it is desirable to minimize recoil. Inaddition, the stent must possess sufficient deformational capability toallow for crimping, expansion, and cyclic loading. Longitudinalflexibility is important to allow the stent to be maneuvered through atortuous vascular path and to enable it to conform to a deployment sitethat may not be linear or may be subject to flexure. Finally, the stentmust be biocompatible so as not to trigger any adverse vascularresponses.

The structure of a stent is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elementsoften referred to in the art as struts, links, crests, or bar arms. Thescaffolding can be formed from wires, tubes, or sheets of materialrolled into a cylindrical shape. The scaffolding is designed so that thestent can be radially compressed (to allow crimping) and radiallyexpanded (to allow deployment). A conventional stent is allowed toexpand and contract through movement of individual structural elementsof a pattern with respect to each other.

Additionally, a medicated stent may be fabricated by coating the surfaceof either a metallic or polymeric scaffolding with a polymeric carrierthat includes an active or bioactive agent or drug. Polymericscaffolding may also serve as a carrier of an active agent or drug.

Coronary stents made from non-erodible metals have become the standardof care for percutaneous coronary intervention (PCI) since such stentshave been shown to be capable of preventing early and later recoil andrestenosis. Despite the positive success of such stents in PCI, adrawback of such durably implanted stents is that the permanentinteraction between the stent and surrounding tissue can pose a risk ofendothelial dysfunction and late thrombosis.

Thus, it may be desirable for a stent to be biodegradable orbioerodible. In the treatment of coronary heart disease with a stent,the presence of the stent in a body is necessary for a limited period oftime until its intended function of, for example, maintaining vascularpatency and/or drug delivery. Therefore, there is a need to addressissues relating to the erosion of a stent made from bioerodablematerials such as bioerodable metals that eventually completely erodeafter the clinical need for them has ended.

SUMMARY OF THE INVENTION

Various embodiment of the present invention include a stent comprising ascaffold composed of a homogeneous or heterogeneous alloy(s) comprisinga magnesium content of 30 to 80 wt % and a zinc or iron content of 10 to70 wt %.

Various embodiment of the present invention include a stent comprising ascaffold composed of plurality of struts, wherein the struts comprise: ashell composed of a first erodible metal; and a core composed of asecond erodible metal surrounded by the shell, wherein the firsterodible metal is slower eroding than the second erodible metal, whereinthe first erodible metal comprises zinc or iron, wherein the seconderodible metal is a magnesium alloy.

A stent comprising a scaffold composed of plurality of struts, whereinthe struts comprise: an abluminal layer and a luminal layer composed ofa first erodible metal; and a middle layer composed of a second erodiblemetal between the abluminal and luminal layers, wherein the firsterodible metal is slower eroding than the second erodible metal, whereinthe first erodible metal comprises zinc or iron, wherein the seconderodible metal is a magnesium alloy.

Various embodiment of the present invention include a stent comprising:a scaffold composed of a magnesium alloy; and a coating layer above thescaffold surface, wherein the coating is composed of an erodible metalthat is slower eroding than the magnesium alloy of the scaffold, whereinthe slower eroding metal is selected from the group consisting of iron,iron alloy, zinc, and zinc alloy, wherein a thickness of the coatinglayer is between 0.1 and 10 microns.

Various embodiment of the present invention include a stent comprising:a scaffold composed of a magnesium alloy; and a coating layer above thescaffold surface, wherein the coating is composed of a biodegradablepolymer, wherein the number average molecular weight (Mn) of the polymeris greater than 500 kDa.

Various embodiment of the present invention include a stent comprising:a scaffold composed at least in part of a mixture of a magnesium alloyand a plurality of elemental calcium particles, wherein the plurality ofelemental calcium particles are dispersed within the magnesium alloy,and wherein the particles have a size between 0.1 and 10 microns and arebetween 5 and 25 wt % of the mixture.

Various embodiment of the present invention include a stent comprising:a scaffold composed at least in part of a mixture of a magnesium alloyand a plurality of particles, wherein the plurality of particles isdispersed within the magnesium alloy, wherein the particles include afirst type of particles and a second type of particles, wherein thefirst type is particles of an inorganic salt of calcium other thancalcium phosphate and the second type is particles of an inorganic saltof phosphate or carbonate other than calcium phosphate or calciumcarbonate, wherein the particles have a size between 0.1 and 5 micronsand are between 5 and 25 wt % of the mixture.

Various embodiment of the present invention include a stent comprising:a scaffold composed of a magnesium alloy; and a coating above thescaffold surface, wherein the coating comprises a bioglass layercomposed of bioglass, wherein the bioglass layer is nonporous and is 0.1to 2 microns in thickness, wherein the coating comprises a second layerabove the bioglass layer composed of a polymer and a drug.

Various embodiment of the present invention include a stent comprising:a scaffold composed of a magnesium alloy; and a coating above thescaffold surface, wherein the coating comprises a hydroxyapatite layercomposed of hydroxyapatite, wherein the hydroxyapatite layer is 0.05 to25 microns in thickness.

Various embodiment of the present invention include a method offabricating a stent comprising: providing a scaffold composed of amagnesium alloy; processing the scaffold to oxidize a surface of thescaffold which forms a layer comprising magnesium oxide; and performinga hydrolysis step to convert the magnesium oxide to magnesium hydroxide;wherein a thickness of the layer is between 0.1 and 10 microns.

Various embodiment of the present invention include a stent comprising:a scaffold composed of a magnesium alloy; and a coating above thescaffold surface, wherein the coating is composed of a magnesium salt ofphosphate or ammonium phosphate, wherein the coating has a thicknessbetween 0.1 and 10 microns.

Various embodiment of the present invention include a method offabricating a stent comprising: providing a scaffold composed of amagnesium alloy; exposing a surface of the scaffold to a solutionincluding ammonium or phosphate ions in the presence of a mineral acidcomprising HCl, H₃PO₄, HClO₄ or H₂SO₄ to oxidize magnesium on thesurface and precipitate a magnesium phosphate or magnesium ammoniumphosphate salt layer on the surface, wherein a thickness of the layer isbetween 0.1 and 10 microns.

Various embodiment of the present invention include a method offabricating a stent comprising: providing a scaffold composed of amagnesium alloy; exposing a surface of the scaffold to a solutionincluding ammonium or phosphate ions in the presence of an oxidizingagent to oxidize magnesium on the surface of the scaffold, wherein athickness of the layer is between 0.1 and 10 microns.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a view of a stent.

FIG. 2A depicts a cross-section of a strut of a stent with a core and ashell surrounding the core.

FIG. 2B depicts an axial cross-section of the strut depicted in FIG. 2A.

FIG. 3A depicts a cross-section of a strut of a stent having anabluminal layer, luminal layer, and a middle layer.

FIG. 3B depicts an axial cross-section of the strut of FIG. 3A.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention relate to stents made frommagnesium or magnesium alloys that include additives or barrier coatingsthat modify the corrosion rate of the stent. These embodiments areapplicable to, but are not limited to, self-expandable stents,balloon-expandable stents, stent-grafts, and generally tubular medicaldevices.

A stent may include a pattern or network of interconnecting structuralelements or struts. FIG. 1 depicts a view of a stent 100. In someembodiments, a stent may include a body, backbone, or scaffolding havinga pattern or network of interconnecting structural elements 105. Stent100 may be formed from a tube (not shown). The structural pattern of thedevice can be of virtually any design. The embodiments disclosed hereinare not limited to stents or to the stent pattern illustrated in FIG. 1.The embodiments are easily applicable to other patterns and otherdevices. The variations in the structure of patterns are virtuallyunlimited.

A stent such as stent 100 may be fabricated from a metallic tube or asheet by rolling and bonding the sheet to form the tube. A tube or sheetcan be formed by drawing, extrusion or casting. A stent pattern, such asthe one pictured in FIG. 1, can be formed in a tube or sheet with atechnique such as laser cutting or chemical etching. The stent can thenbe crimped on to a balloon or catheter for delivery into a bodily lumen.

The embodiments of the stents of the present invention can be designedfor the localized delivery of a therapeutic agent. A medicated stent maybe constructed by coating the substrate or scaffold with a coatingmaterial containing a therapeutic agent. The substrate of the device mayalso contain a therapeutic agent.

While stents have typically been constructed of relatively inert metalsin order to ensure their longevity, degradable or erodible stentstructures have more recently been devised in an effort to providesupport for only a limited period of time. In general, the support orpatency provided by a stent for the treatment of a stenosis is requiredonly for a limited period of time. For example, a preferred or requiredtreatment time by a stent may be less than 18 months, less than a year,between three and 12 months, or more narrowly, between four and eightmonths.

Once the stent, erodible or nonerodible, is deployed in vessel, thestent is required to maintain patency of the vessel which corresponds tosupporting the vessel at or close to the deployed diameter for a periodof time to allow for remodeling of the vessel wall. To accomplish this,the stent should be capable of applying an outward radial force tocounter the inward radial force imposed by the vessel wall, includingthe cyclic loading induced by the beating heart. In the case of anerodible stent, the stent should maintain such patency in spite of thedegradation or erosion of the stent body for a period of time. Thus, thestent should have sufficient strength, stiffness (modulus) to maintainpatency of the vessel wall.

Furthermore, the stent should be sufficiently tough to resist failure orfracture of the structural elements of a stent. One measure of toughnessis the area under a stress-strain or load elongation curve from zerostrain to the strain at fracture. Therefore, the modulus, stress atfailure (strength), and elongation at failure are relevant to thetoughness of a metal or alloy. The bending regions of a typical stentstructure are the most susceptible to failure during use. Therefore, anerodible stent structure should have the appropriate combination ofmechanical properties and degradation or erosion properties to providepatency during a specified treatment period.

The terms degrade, absorb, erode, as well as degraded, absorbed, eroded,are used interchangeably and refer to materials that are capable ofbeing completely eroded, or absorbed when exposed to bodily conditions.Such materials may be capable of being gradually resorbed, absorbed,and/or eliminated by the body.

“Corrosion” generally refers to the deterioration of essentialproperties in a metal due to reactions with its surroundings. Corrosionof a metal can occur upon contact with a variety of materials includingair, water, organic solvents, etc. As it is used herein, corrosionrefers to deterioration or degradation of a metal due to contact withwater, such as bodily fluids containing water in a vascular environment.The degradation can result in deterioration of mechanical properties ofa metallic construct and mass loss from the construct.

Corrosion in an environment that contains moisture involves a series ofreactions that first result in the formation of metal ions, and secondlylead to removal of metal atoms from the metal surface. Corrosionresulting from contact with bodily fluids containing water results inoxidation of the metal (loss of electron(s)) as the metal reacts withwater and oxygen. The metal atoms at the surface lose electrons andbecome positively charged ions that leave the metal to form salts insolution. Corrosion reactions generally involve both oxidation andreduction reactions. The metal is oxidized with subsequent reduction ofhydrogen ions and oxygen in solution. The reduction reactions drive theoxidation reactions.

Many erodible metals and metal alloys, such as magnesium, iron, zinc,tungsten, and their alloys, may be promising as stent materials.However, these and other metals may not provide a desired combination ofdegradation and mechanical behavior for a stent during a desiredtreatment period. In particular, certain metals, such as magnesium, maydegrade too quickly, exhibiting a corrosion that is faster than isdesired. Specifically, as the stent corrodes the radial strength, aswell as other mechanical properties, decreases. Eventually the stentreaches radial strength that can no longer maintain patency. Therefore,metals that corrode too fast may not provide radial strength thatmaintains patency for a period of time required for remodeling of thevessel wall.

An exemplary desired degree of patency is no less than 50% of thedeployed diameter of the stent. It is believed that radial strengthshould be maintained for at least 3 months after implantation to achievethe desired degree of stabilization and remodeling of the vessel wall. Alate lumen loss that is higher than desired demonstrated in a clinicalsetting may be indicative that radial strength is not maintained for asufficient period of time.

Heublein et al. conducted a series of in vitro and in vivo preclinicaltrials using stents made of magnesium alloy. Heublein, B. et al. Heart2003; 89:651-656. These studies demonstrated relatively high rates ofdegradation from 60 to 90 days, with loss of mechanical integrity atbetween 36 and 56 days after implantation and complete stent degradationestimated at 89 days. Heublein, B. et al. Heart 2003; 89:651-656 Aclinical study initiated in 2005 using a magnesium alloy stent showedafter four months a late lumen loss of 0.83 mm and also that stentstruts were not visible, indicating complete degradation of thescaffold. Erbel, R. et al., Lancet vol. 369, Jun. 2, 2007.

Another generation of magnesium alloy scaffolds has been developed bythe same company as the stent that was the subject of the trialsdescribed in Erbel et al. This stent is described as having a refinedalloy that erodes slower than that of the previous generation stent. Theclinical results reported for this second trial showed that the lateloss at 6 months was as high as 0.68 mm. This level of late loss forthis magnesium alloy stent suggests a premature loss of mechanicalsupport of scaffold. One way to address this premature loss is areduction in the corrosion rate of the scaffold.

Thus, approaches are needed for adjusting, controlling, modifying, ortailoring the in vivo erosion rates and mechanical properties oferodible metallic stents, in particular stents made of magnesium alloys.It is desirable to adjust the erosion rate of the stent withoutunacceptably compromising properties such as radial strength orbiocompatibility.

A stent body, scaffolding, or substrate can refer to a stent structurewith an outer surface to which no coating or layer of material differentfrom that of which the structure is manufactured. If the body ismanufactured by a coating process, the stent body can refer to a stateprior to application of additional coating layers of different material.By “outer surface” is meant any surface however spatially oriented thatis in contact with bodily tissue or fluids. A stent body, scaffolding,or substrate can refer to a stent structure formed by laser cutting apattern into a tube or a sheet that has been rolled into a cylindricalshape.

Some embodiments of controlling the corrosion rate of erodible metalstents can include an alloy that includes magnesium or a magnesium alloymixed with slower eroding metals. Such slower eroding metals includeiron or zinc. The alloys of the present invention can include at least10% elemental zinc or iron.

In exemplary embodiments, the magnesium alloys can be between 10 and 70wt %, 10 to 20 wt %, 20 to 30 wt %, 30 to 40 wt %, 40 to 50 wt %, and 50to 70 wt % elemental iron or zinc content. The alloy can include 30 to90 wt % magnesium, or more narrowly, 30 to 40 wt %, 40 to 50 wt %, 50 to70 wt %, or 70 to 90 wt % magnesium. The alloys can include lesserpercentages of other metals (e.g., less 10%) such as aluminum, gallium,zirconium, manganese, silicon, bismuth, and neodymium. The alloys can befree of any of the metals disclosed herein, other than magnesium. Thealloys may be nonporous, porous, drug-free, or contain a drug. Thealloys can have 0.1 to 1%, 1 to 2%, 1 to 5%, 2 to 5%, less than 1%, lessthan 2%, or less than 5% porosity. Porosity is defined as the ratio ofvoid volume to total volume of a material and the total volume doesinclude the volume of gaps in between structural elements of a stentstructure. The scaffold may be formed completely of the alloys.

In these embodiments, the magnesium alloys can be a complete solidsolution or a partial solid solution, resulting in homogeneous alloywith a single phase. Alternatively, the magnesium alloys can beheterogeneous alloys containing multiple phases with interstitialstructure as an example. The multiple phases can include a phasecomposed of magnesium or magnesium alloy having up to 5 wt % of iron orzinc or 1 to 5 wt % of iron or zinc. The multiple phases can include aphase composed primarily or completely of zinc or iron.

The alloys with high content of iron or zinc can be prepared by meltingand mixing magnesium or magnesium alloy, iron or zinc and otherelements, for example in a vacuum induction furnace under argonatmosphere. Tubing can be formed from the resulting ingot and a scaffoldmay be obtained from mixture tubing by laser cutting the tube.

In further embodiments, an erodible metal stent can include a scaffoldcomposed of struts having a structure that includes a core and an outershell. The shell is composed of a metal that is slower eroding than thecore. The core is made of a magnesium alloy and the shell is composed ofa metal that is slower eroding than the core magnesium or magnesiumalloy.

The slower eroding metal can include iron, iron-magnesium alloy, ironalloy, zinc, zinc magnesium alloy, and zinc alloy. A ratio of athickness of the core to the shell may be between 10:1 and 2:1. Thethickness of the shell can be 2 to 50 microns.

FIG. 2A depicts a cross-section of a strut 120. FIG. 2B depicts an axialcross-section of strut 120. Strut 120 has a luminal surface 124 and anabluminal surface 126 and a side wall surfaces 128. Strut 120 has a core130 surrounded by an outer shell 132. Core 130 has a thickness in theradial direction Tc and shell 132 has a thickness Ts. Core 130 has awidth We that may be different from Tc if the strut is not square incross section.

A scaffold composed of struts with a core and shell of different metalsmay be made by making the struts separately and welding them togetherinto a scaffold pattern. Alternatively, a tube made of the core metalmaterial may be laser machined to form the scaffold pattern. Thescaffold pattern then may be coated with the shell metal material usingvarious methods such as plasma deposition, electroplating, sputtercoating, or vacuum evaporation.

In another methodology, a core and shell strut is formed by drawing wirecomposed of a core and a shell. The resulting wire can have anycross-sectional shape including square, rectangular, round, or oval.This wire is then fabricated into a stent by cutting the wire intosegments, forming the segments into rings and welding them closed,stamping crests into the rings, and welding the rings together atselected points to form a stent. Otherwise, the wire may be formed intoa continuous sinusoid, this sinusoid is wrapped around a mandrel to forma helix, and the rows of the helix welded to together at selected pointsto form a stent.

In other embodiments, the struts of a scaffold of a stent can include anabluminal layer, a luminal layer, and a middle layer between theabluminal and luminal layers. The middle layer is magnesium or amagnesium alloy. The abluminal and luminal layers are composed of ametal that is slower eroding than the middle layer of magnesium ormagnesium alloy. The abluminal and luminal layers may have the samecomposition or may have different composition. A ratio of a thickness ofthe core to a luminal or abluminal layer may be between 20:1 and 4:1.The thickness a luminal or abluminal layer can be 2 to 30 microns, ormore narrowly, 10 to 20 microns, or 20 to 30 microns.

FIG. 3A depicts a cross-section of a strut 140. FIG. 3B depicts an axialcross-section of strut 140. Strut 140 has a luminal surface 144 and anabluminal surface 146 and a side wall surface 148. Strut 140 has amiddle layer 150 which is between a luminal layer 152 and an abluminallayer 154. Middle layer 150 has a thickness Tm and luminal layer 152 andabluminal layer 154 have a thickness To.

The three-layer tube with magnesium alloy in the middle and the sloweroding metals layers can be manufactured by co-extrusion. Such a tubedrawing process could be applied with a magnesium alloy as the innerlayer. The extruded tubing may then be machined to form a scaffold.Alternatively, the three layer scaffold can be made from threeconcentric tubes. The inner and outer tubes are made of the slow erodingmetal and the middle tube is made of the magnesium alloy. Additionally,to cover the exposed side walls, the three layer scaffold can be coatedwith a slow eroding metal.

The core or middle layer of the two sets of embodiments above can bemade from pure magnesium or a magnesium single phase or multi-phasealloy with a magnesium content of 30 to 99 wt %, or more narrowly, 50 to90 wt %, 60 to 90 wt %, or 70 to 90 wt %. The middle layer can have zincor iron content of 10 to 70 wt %.

The slow eroding metal of the shell or abluminal/luminal layers may bepure zinc or pure iron. The slow eroding metal can be a single phase ormulti-phase alloy including 10 to 100 wt % of iron or zinc, or morenarrowly 10 to 70 wt %, 10 to 20 wt %, 20 to 40 wt %, 40 to 60 wt %, 60to 80 wt % zinc or iron content.

Upon implantation of the stent embodiments described, the slow erodingshell or abluminal/luminal layers prevent, reduce, inhibit exposure ofthe core or middle layer to bodily fluids so that erosion of the core isdelayed. Therefore, the shell or outer layers slow the erosion rate andthe degradation of mechanical properties, such as radial strength.

In further embodiments, an erodible metal scaffold composed of magnesiumor magnesium alloy can have a thin slower erodible metal coating overall or some of the scaffold as a moisture barrier to delay erosion ofthe scaffold. The slower eroding metal of the coating includes iron,iron alloy, zinc, or zinc alloy.

The slower eroding metal may have a thickness of 0.01 to 10 microns, ormore narrowly, 0.1 to 5, 1 to 5 microns, about 1 micron, about 2microns, or about 3 microns. The slow eroding metal layer may be all ormostly elemental metal(s). The slow eroding metal layer may be free ofmetal oxides or may have less then 1 wt %, 2 wt %, or less than 5 wt %oxides. The slow eroding metal layer may be free of metal compoundsother than oxides or may have less then 1 wt %, 2 wt %, or less than 5wt % other metal compounds other than oxides. The slower eroding metallayer may be nonporous or have less than 1%, less than 2%, or less than5% porosity.

Methods of coating the magnesium alloy scaffold with the slow erodingmetal include electroplating, electroless deposition, chemical vapordeposition, sputter coating, and vacuum evaporation techniques.

The slow eroding metal of the shell or abluminal/luminal layers may bepure zinc or pure iron. The slow eroding metal can be an alloy including10 to 100 wt % of iron or zinc, or more narrowly 10 to 70 wt %, 10 to 20wt %, 20 to 40 wt %, 40 to 60 wt %, 60 to 80 wt % zinc or iron content.

In another embodiment, a barrier layer over magnesium or magnesium alloyscaffold includes a biodegradable polymer. The polymer can have amolecular weight 10 to 100 kDa, 50 to 70 kDA, 60 to 100 kDa, 100 to 150kDa, 100 to 200 kDa, greater than 10 KDa, 300 kDa, 400 kDa, 500 kDa, 700kDa, or greater than 1000 kDa. The molecular weight may refer to eithernumber average molecular weight or weight average molecular weight.

The biodegradable polymer may be a semicrystalline polymer. Thebiodegradable polymer may also be a bulk-eroding semicrystallinepolymer.

A bulk-eroding polymer refers to a polymer that degrades in the bulk ofthe polymer below a moisture contacting surface. Water can penetrateinto a bulk eroding polymer before moisture-contacting surface regionserode away from the polymer. This allows chemical degradation (e.g.,chain scission due to hydrolysis) of the polymer to occur throughoutmost or the entire polymer prior to complete erosion of the polymer.Therefore, the bulk eroding polymer may allow some contact of moisturewith the metal scaffold surface prior to disappearance of the barrierlayer.

The biodegradable polymer may contain a drug or may be drug-free. Thepolymer layer may be nonporous or may have a porosity of 1 to 5%, lessthan 1% or less than 5%.

The biodegradable polymer coating with and without crystallinity haswater absorption less than 5%, less than 2%, preferable less than 1%before implant.

The polymer layer may be disposed over the scaffold body by varioustechniques including spray coating, dip coating, or roll coating. Thethickness of the layer can be from 0.2 up to 10 microns, or morenarrowly, 1 to 5 microns, 2 to 3 microns, about 3 microns, or about 2microns.

After the deposition of a semicrystalline polymer on a magnesium alloyscaffold, the coating layer may be annealed to increase thecrystallinity. The increased crystallinity increases the resistance ofwater or moisture penetration. The crystallinity of the polymer layermay be greater than 20%, 30%, 40%, 50%, or 60%. The crystallinity of thepolymer layer may be 20 to 60%, 30 to 60%, 40 to 50%, 50 to 60%, 30 to50%, or 40 to 50%.

The polymer of the biodegradable layer may be a biodegradable aliphaticpolyester. The non-exclusive examples of biodegradable polymers caninclude poly(L-lactide), poly(D-lactide), poly(D,L-lactide),polyglycolide, polycaprolactone, poly(trimethylene carbonate),poly(hydroxyl alkanoate), poly(butylene succinate). Additionalbiodegradable polymers include L-tyrosine-derived polyarylates such aspoly(HTH sebacate), poly(DTO sebacate), poly(DTO succinate), poly(DTBsuccinate), poly(DTO adipate), poly(HTE adipate), poly(DTH suberate),poly(DTM sebacate), poly(DTM adipate), poly(DTB glutarate), poly(HTHadipate), poly(DTH adipate), poly(DTB adipate), poly(DTsB sebacate), andpoly(DTE glutarate).

Biodegradable polymers with a low water uptake are preferred to delaycorrosion of the magnesium or magnesium alloy scaffold. The water uptakeof biodegradable polymers has been studied by Valenzuela et al. J. ofAppl. Pol. Sci., Vol. 121, 1311-1320 (2011). The polymer may have apercent water uptake of 1 to 5 wt %, 1 to 10 wt %, 5 to 10 wt %, 5 to 20wt %, 10 to 20 wt %, less than 5 wt %, less than 10 wt %, or less than20 wt %. The water uptake can refer to in vitro equilibration in aqueoussolutions or in vivo, or water uptake in such conditions at least up to28 days or 3 months. The molecular weight, weight or number average, canbe selected to have the selected water uptake.

Further embodiments of the present invention include a magnesium ormagnesium alloy scaffold that includes particulate additives thatcontrol, modify, or adjust the erosion rate of the scaffold. Suchparticulate additives may be dispersed in part or all of the metal ofthe scaffold. The particles can be dispersed uniformly or homogeneouslythroughout the scaffold or a region of the scaffold. The additives mayreduce the corrosion rate of the metal of magnesium or magnesium alloyof the scaffold. Particulate additives do not refer to elements orcompounds mixed in a metal or alloy on an atomic or molecular level. Thesize of the particles may be from 0.01 to 0.1 micron, 0.1 to 10 microns,0.1 to 1 micron, 1 to 3 microns, 0.1 to 5 microns, 1 to 5 microns, or 1to 10 microns.

In some embodiments, particulate additives include particles of calciummetal dispersed with the magnesium or magnesium alloy of a scaffold. Thecalcium particle content may be 0.5 to 25 wt %, or more narrowly 0.5 to10 wt %, 1 to 10 wt %, 1 to 5 wt %, 5 to 10 wt %, or 10 to 20 wt % ofthe scaffold, the alloy-particle mixture, or a portion of the scaffold.The metal of the scaffold may be free of calcium compounds other thanelemental calcium or may have less than 1 wt %, 2 wt %, or less than 5wt % of such compounds.

In some embodiments, the entire scaffold can be made of thealloy-particle mixture. In other embodiments, a portion of the scaffoldcan be made of the alloy-particle mixture. In one embodiment, thescaffold structure can include a core of magnesium alloy with a shellcomposed of the alloy-particle mixture, as depicted in FIG. 2. The corecan be free of the calcium particles. The above-mentioned dimensions forthe core and shell apply this embodiment.

Alternatively, the scaffold structure can include luminal and abluminallayers composed of the alloy-particle mixture and a middle layer betweenthese layers, as depicted in FIG. 3. The middle layer can be free of thecalcium particles.

In another embodiment, a magnesium alloy scaffold that may be free ofthe calcium particles and can include an alloy-calcium particle mixturecoating over all or part of the scaffold. Such a coating may have athickness of 1 to 5 microns, 1 to 10 microns, or 5 to 10 microns.

When a scaffold including an alloy-calcium particles mixture isimplanted, the scaffold is exposed to bodily fluids and degrades and themetallic calcium in the alloy is converted quickly to Ca²⁺ ions at theparticle-fluid interface. Calcium is more electropositive than magnesiumand will preferentially be oxidized when exposed to water and oxygen. Indoing so, the calcium will protect the magnesium from oxidation. Theparticles may also be released.

Bodily fluids, such as blood, are saturated or nearly saturated withcalcium. The larger calcium concentration at the alloy or particlesurface will cause precipitation of calcium phosphate and calciumcarbonate salts. These salts, which include calcium phosphate (Ca₂P0₄),hydroxyapatite (Ca₁₀(P0₄)₆(OH)₂), and calcium carbonate (CaCO₃) willform an insoluble or low solubility layer on the surface of the alloy,slowing its degradation.

Calcium has a melting point of 839 deg C. versus magnesium at 650 deg C.Thus, calcium particles may be dispersed in magnesium or magnesium alloythrough melt processing, such as tube extrusion. The scaffold can thenbe laser machined from the tube.

Further particulate additives for controlling erosion of a magnesium ormagnesium alloy scaffold can include particles of inorganic salts. Theparticles can include inorganic salts of calcium, inorganic salts ofphosphate, and inorganic salts of carbonate. The scaffold can includecombinations of any of the above.

The scaffold can include particle combinations of calcium salts otherthan calcium phosphate and phosphate salts other than calcium phosphate.The scaffold can include particle combinations of calcium salts otherthan with calcium phosphate and carbonate salts other than with calcium.

Exemplary calcium salts include CaCl₂, CaBr₂, Ca(OH)₂, CaSO₄. Exemplaryphosphate salts include Na₃PO₄, Na₂HPO₄, NaH₂PO₄, K₃PO₄, K₂HPO₄, KH₂PO₄,and Mg₃(PO₄)₂. Exemplary carbonate salts include CaCO₃, NaHCO₃, Na₂CO₃,KHCO₃, K₂CO₃, LiHCO₃, CaMg(CO₃)₂, and Li₂CO₃.

In a manner similar to the calcium particle embodiments, the entirescaffold can be made of the alloy-particle mixture, the scaffoldstructure can include a core of magnesium alloy with a shell composed ofthe alloy-particle mixture, or the scaffold structure can includeluminal and abluminal layers composed of the alloy-particle mixture anda middle layer between these layers.

The inorganic particle content may be 0.5 to 25 wt %, or more narrowly0.5 to 10 wt %, 1 to 10 wt %, 1 to 5 wt %, 5 to 10 wt %, or 10 to 20 wt% of the scaffold, the alloy-particle mixture, or a portion of thescaffold. The metal of the scaffold may be free of one or more of thesalts disclosed herein or may have less than 1 wt %, 2 wt %, or lessthan 5 wt % of such compounds.

Particles of the inorganic salts may be added to a magnesium alloyduring melt processing of the alloy. Thus, the inorganic salt particlesmay be dispersed in a magnesium or magnesium alloy through meltprocessing, such as tube extrusion. The scaffold can then be lasermachined from the tube.

In further embodiments, a magnesium or magnesium alloy scaffold caninclude a bioglass layer over the scaffold as a moisture barrier.Bioglass refers to bioresorbable glass ceramics composed of SiO₂, Na₂O,CaO, and P₂O₅ in specific proportions. Commercially available glassceramics include Bioglass® derived from certain compositions ofSiO₂—Na₂O—K₂O—CaO—MgO—P₂O₅ systems. Some commercially available glassceramics include, but are not limited to:

45S5: 46.1 mol % SiO₂, 26.9 mol % CaO, 24.4 mol % Na₂O and 2.5 mol %P₂O₅;

58S: 60 mol % SiO₂, 36 mol % CaO, and 4 mol % P₂O₅; and

S70C30: 70 mol % SiO₂, 30 mol % CaO.

The bioglass coatings can be above or over all or a portion of themagnesium or magnesium alloy scaffold. The thickness of the bioglasscoating can be less than 5 microns, less than 2 microns, or less than 1micron. The thickness of the bioglass coating can be 0.1 to 5 microns,0.1 to 2 microns, 1 to 2 microns, 1 to 3 microns, about 2 microns, orabout 3 microns. A relatively thin coating is preferable since a thinnercoating of bioglass can be flexible, rather than brittle. Thus, thecoating may be sufficiently thin that cracking is reduced or eliminatedduring use such as when the stent is crimped or expanded to a deployedconfiguration.

The bioglass coating may be nonporous or have a porosity less than 1%,less than 2%, or less than 5% porosity. The bioglass layer may also befree of drugs or therapeutic agents. The bioglass layer may also be freeof particulates. The bioglass material of the bioglass layer may also bein non-particulate form.

Another embodiment of a protective coating on the magnesium alloyscaffold is addition of a hydroxyapatite coating over the scaffold. Theprotection is dependent on the thickness of hydroxyapatite (HA) layer.The HA coating can be applied via dip coating of HA fine powder slurry(followed by high temperature sintering), sputter coating, pulse laserdeposition, an electrophoretic deposition (followed by sintering),plasma spraying, thermal spraying and sol-gel process. The thickness ofa HA coating layer may be from 0.05 to 25 microns, or more narrowly,from 5 to 10 microns and is dependent on the application method. The HAcoating layer may be nonporous or porous. The coating layer can have 0.1to 1%, 1 to 2%, 1 to 5%, 2 to 5%, less than 1%, less than 2%, or lessthan 5% porosity. The coating layer may be drug-free or contain a drug.

Further embodiments of a barrier layer over a magnesium or magnesiumalloy scaffold includes a layer including or composed of magnesiumoxide, magnesium hydroxide, or both. An oxide layer can be formed on ascaffold using various methods including electro-chemical, plasma,micro-arc oxidation, ozone treatment, corona discharge, and alkalinesolution treatment.

In an electro-chemical treatment, the magnesium alloy acts as the anode,resulting in oxidation of a surface layer of the scaffold. Plasmatreatment refers to the treatment of materials with low-temperatureplasmas generated in arc or high-frequency plasmatrons. Plasma is anysubstance (usually a gas) whose atoms have one or more electronsdetached and therefore become ionized. The detached electrons remain,however, in the gas volume that in an overall sense remains electricallyneutral. Thus, any ionized gas that is composed of nearly equal numbersof negative and positive ions is called plasma.

Corona discharge treatment refers to a surface modification techniquethat uses a low temperature corona discharge plasma to impart changes inthe properties of a surface. The corona plasma is generated by theapplication of high voltage to sharp electrode tips which forms plasmaat the ends of the sharp tips. A linear array of electrodes is oftenused to create a curtain of corona plasma.

The oxidation step can form a layer that includes compounds such asMg(OH)₂, MgO, or Mg—O_(n)—X (where X is some other metal such as Zn, Al,Si, etc.). The compounds formed depend on the conditions, and thepresence of water in the process. Temperatures above 340° C. favor theformation of magnesium oxide, while temperature below this allow for theformation of the less water soluble magnesium hydroxide. The thicknessof the oxide layer can be 0.1 to 10 microns, or more narrowly, 0.1 to 5microns, 1 to 5 microns, 2 to 3 microns, about 2 microns, or about 3microns.

The plasma treatment can include oxygen, air, or water plasma treatment.The corona discharge treatment may be at atmospheric pressure. Thealkaline solution treatment may be performed with sodium hydroxide,potassium hydroxide, trisodium phosphate, ammonium hydroxide, sodiumcarbonate, sodium bicarbonate, sodium borate, magnesium carbonate, andthe mixtures thereof.

The scaffold may further be treated with a hydrolysis step to convertsurface MgO to Mg(OH)₂. The hydrolysis step can include exposing theoxidized surface to moisture. This hydrolysis reaction can be done withsteam at elevated temperature and pressure for a period of hours. Forexample, the temperature ranges can include 100 to 150 deg C., 150 to250 deg C., or greater than 200 deg C. The pressure ranges can include 1to 2 atm, 2 to 3 atm, or greater than 3 atm. It can also be done byexposing the scaffold to aqueous solution at neutral or basic pH.

Furthermore, a heat treatment step can be performed on the scaffold. Theheat treatment step can be performed on the scaffold between thetreatment that oxidizes the scaffold and the treatment converting theMgO to Mg(OH)₂. The heat treatment step consolidates and increases thedensity of the oxide layer, removes bound water, and thickens the oxidelayer. The heat treatment step can be performed between the oxidationstep and the hydrolysis step, after the hydrolysis step, or both. Theheat treatment step may be performed by exposing the scaffold to hightemperatures in a forced air convention oven, vacuum oven, or heatedoven with inert atmosphere. The exposure temperature can be 40 to 340deg C., 160 to 300 deg C., 80 to 25000 deg C., or 100 to 200 deg C.

In further embodiments, a magnesium or magnesium alloy scaffold includesa barrier layer of a water insoluble or very low water soluble magnesiumsalt on a surface of the scaffold. The layer may be over all or aportion of the scaffold. Exemplary magnesium salts include magnesiumhydroxide (Mg(OH)₂), magnesium ammonium phosphate (MgNH₄PO₄), ormagnesium phosphate (Mg₃(P0₄)₂). The solubility product constant foreach of these salts is shown in Table 1.

TABLE 1 Magnesium salts for barrier layer. Magnesium Solubility SaltProduct Constant Reagent Used to Make Salt Mg(OH)₂ 1.8 × 10⁻¹¹ WaterMgNH₄PO₄ 2.5 × 10⁻¹³ NH₄H₂PO₄, NH₄ ⁴⁻ + PO₄ ³⁻ + oxidizer Mg₃(PO₄)₂  1 ×10⁻²⁵ Phosphoric Acid (H₃PO₄), PO₄ ³⁻ + oxidizer

A very low solubility salt layer is preferred since it protects thescaffold from corrosion for a longer period of time. The slower thedissolution rate of the coating, the longer the corrosion of thescaffold is delayed. As shown in Table 1, MgNH₄PO₄ and Mg₃(P0₄)₂ have amuch lower solubility than Mg(OH)₂. Salts which are less soluble thanthe naturally forming magnesium hydroxide are advantageous.

The magnesium salt layer can have a thickness of 0.1 to 10 microns, 0.1to 5 microns, 1 to 5 microns, 2 to 3 microns, about 2 microns, or about3 microns. The composition of the layer can be 100% of the magnesiumsalt. The composition of the layer can be 80 to 90 wt %, 90 to 95 wt %,or 95 to 99 wt % of the salt. The salt layer may be nonporous or haveless than 1%, less than 2%, or less than 5% porosity. The salt layer maybe drug-free.

The protective salt layer can be formed through precipitation of themagnesium salt on the surface of the magnesium or magnesium alloyscaffold. Coatings of these salts can be formed by exposing themagnesium alloy to dilute solutions of the acids listed in the table. Inthis case, the acid itself is the oxidizer, and hydrogen gas is formedby an oxidation-reduction reaction. Another approach is to expose the Mgalloy surface to phosphate or ammonium ions in an acidic solution wherethe low pH is not produced by phosphoric acid but by another mineralacid such as HCl or H₂SO₄. The pH should be low enough for the reactionto proceed, oxidizing some magnesium and forming the MgNH₄PO₄, orMg₃(PO₄)₂ precipitate on the surface.

Another technique of making the coatings is to expose the Mg alloysurface to the necessary ions such as ammonium or phosphate in thepresence of an oxidizer to oxidize the magnesium. In this case, thesolution need not be at acidic pH with H₃O⁺ as the oxidizer which is thesituation when using dilute solutions of acids. The oxidizer may bedissolved oxygen, ozone, hydrogen peroxide, periodate, persulfate,permanganate, chromium oxide, perchlorate, chlorine, or hypochlorite,

Additionally, a heat treatment, as described above, may also be appliedto the scaffold with the salt coating further solidifying the magnesiumsalt on the surface.

A drug or drugs can be mixed with the protection coating. Thenon-exclusive list of the drugs include those that have the propertiesof anti-proliferative agents, anti-inflammatory agents, antineoplasticagents, antiplatelet agents, anti-coagulant agents, anti-fibrin agents,antithrombonic agents, antimitotic agents, antibiotic agents,antiallergic agents, antioxidant agents as well as cystostatic agents.The coatings or scaffolds of the present invention can include anycombination of the drugs or types of agents disclosed herein. Thecoatings or scaffolds of the present invention can exclude anycombination of the drugs or types of agents disclosed herein.

Exemplary drugs include clobetasol, or derivatives and analogs, alltaxoids such as taxols, docetaxel, and paclitaxel, paclitaxelderivatives, all mTOR binding drugs such as macrolide antibiotics,rapamycin, everolimus, structural derivatives and functional analoguesof rapamycin, structural derivatives and functional analogues ofeverolimus, temsirolimus, deforolimus, myolimus, novolimus, FKBP-12mediated mTOR inhibitors, biolimus, perfenidone, prodrugs thereof,co-drugs thereof, and combinations thereof. Representative rapamycinderivatives include 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578 manufactured by AbbottLaboratories, Abbott Park, Illinois), prodrugs thereof, co-drugsthereof, and combinations thereof.

Any of the above embodiments of scaffolds and scaffolds with protectiveor barrier coatings can further include a polymer coating over all or aportion of the surface of the scaffolds. The polymer of the polymercoating can be bioabsorbable. The polymer can be bulk eroding or surfaceeroding. The polymer can be an aliphatic polyester, such as apoly(L-lactide)-based polymer.

The coating can include a drug or drugs mixed, dispersed, or associatedwith the coating polymer. The polymer coating can have a thickness of 1to 20 microns, less than 2 microns, less than 5 microns, 1 to 10microns, 1 to 5 microns, 2 to 3 microns, about 2 microns, or about 3microns.

Exemplary polymers for a polymer coating include poly(L-lactide),poly(D,L-lactide), poly(D-lactide), poly(D,L-lactide-co-glycolide),poly(D,L-lactide-co-L-lactide), poly(glycolide),poly(L-lactide-co-glycolide), poly(caprolactone), poly(L-lactide-cocaprolactone), poly(D,L-lactide-co-caprolactone), andpoly(glycolide-co-caprolactone). Other useful resorbable polymersinclude poly(ester-amide) copolymers, polycarbonate-ester copolymer suchas poly(L-lactide-co-trimethylene carbonate), poly(orthoesters),poly(anhydrides), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate),poly(4hydroxyvalerate), and poly(hydroxybutyrate-co-hydroxyvalerate).

In exemplary embodiments, magnesium can be alloyed with small of amountsof zinc, sodium, iron, potassium, calcium, aluminum, manganese, bismuth,silver, zirconium, thorium, yttrium, and rhenium. In some exemplaryembodiments, the magnesium composition can be greater than 85%, 90%,95%, or greater than 99% of the alloy. For example, AZ91 magnesium alloyincludes magnesium (89.8%), aluminum (9%), zinc (2%), and manganese(0.2%). In other commercial embodiments, magnesium can be alloyed withlithium with a magnesium-lithium ratio in the range of 60:40. Othermagnesium alloys include AM50A and AE42. Additionally, zinc can bealloyed with titanium (0.1-1%) to improve fracture toughness since zincis a comparatively brittle material.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A stent comprising: a scaffold composed at least in part of a mixtureof a magnesium alloy and a plurality of elemental calcium particles,wherein the plurality of elemental calcium particles are dispersedwithin the magnesium alloy, and wherein the elemental calcium particleshave a size between 0.1 and 10 microns and are between 0.5 and 25 wt %of the mixture.
 2. The stent of claim 1, wherein struts of the scaffoldcomprise a shell region composed of the mixture surrounding a coreregion comprising a magnesium alloy.
 3. The stent of claim 1, whereinstruts of the scaffold comprise a luminal layer and an abluminal layercomposed of the mixture and a middle layer between the luminal andabluminal layer comprising a magnesium alloy.
 4. The stent of claim 1,wherein struts of the scaffold are composed entirely of the mixture. 5.The stent of claim 1, wherein the scaffold comprises struts composed ofmagnesium alloy and a coating composed of the mixture over all or partof the struts.
 6. The stent of claim 5, wherein the coating has athickness of 1 to 5 microns.
 7. The stent of claim 1, wherein theelemental calcium particles are 1 to 10 wt % of the mixture.
 8. Thestent of claim 1, wherein the mixture is free of calcium compounds otherthan the elemental calcium particles.
 9. The stent of claim 1, whereinthe mixture has less than 2 wt % of calcium compounds other than theelemental calcium particles.
 10. A method of treatment comprisingimplanting the stent of claim 1 in a blood vessel, wherein upon exposureto bodily fluids, the scaffold degrades and elemental calcium in theelemental calcium particles is converted to calcium ions at an elementalcalcium particle-fluid interface, wherein the calcium ions arepreferentially oxidized over magnesium when exposed to the bodily fluidsand oxygen, and wherein the oxidized calcium protects the magnesium fromoxidation.
 11. The method of claim 10, wherein a concentration ofcalcium ions at the scaffold surface causes precipitation of calciumphosphate and calcium carbonate salts including calcium phosphate(Ca₂P0₄), hydroxyapatite (Ca₁₀(P0₄)₆(OH)₂), and calcium carbonate(CaCO₃), wherein the precipitated phosphate and calcium carbonate saltsform an insoluble or low solubility layer on the scaffold surface whichslows its degradation.
 12. A method of fabricating the stent of claim 1comprising dispersing the elemental calcium particles in the magnesiumalloy during extrusion of a tube and laser machining the tube to formthe scaffold.